In less than 30 years, 350-400 million people are projected to be affected by Type 2 Diabetes Mellitus (T2DM). Management of the disease hinges on blood tests for glucose, insulin, lipids, and other metabolic variables;unfortunately, these tests are often painful and may be impractical. We propose a non-invasive approach to monitoring glucose regulation via the analysis of volatile organic compounds (VOCs) in exhaled breath. Our general premise is that in T2DM, important changes may occur in the exhaled patterns of VOCs, reflecting endogenous metabolic changes at the tissue and cellular levels. Our main objectives will be two-fold: (1) define differences in exhaled breath gas profiles between healthy and T2DM individuals during experimental fluctuations of plasma glucose, insulin, and free fatty acids and derive breath-based predictions of these circulating variables;(2) investigate novel mechanisms of gas-cell interactions relevant to the pathogenesis of diabetes complications, VOC emission and functional response patterns in neutrophils. The downstream evolution of this project may have a tangible, clinically applicable impact on diabetic populations, as our findings will constitute the basis for the translation of this technology into portable breath analyzers that could replace current blood-based bioassays and provide additional insight on immunofunctionality and glucoregulation that is not possible with modern clinical methodologies. We also envision that easier glucose testing will result in more frequent monitoring and better glycemic control in millions of diabetic patients. Large population screenings, including breath tests for not only glucose but also insulin and lipids, could also be conducted in populations for which blood draws would be difficult, allowing earlier detection and better prevention strategies to ultimately reduce overall health-related costs. PUBLIC HEALTH RELEVANCE: The prevalence of diabetes mellitus worldwide has been rapidly increasing from 171 million patients in 2000 to a projected 366 million people by 2030 (Diabetes Care 2004:1047). We propose that breath gas analysis can be used to measure systemic sugar (and other crucial variables such as insulin and cholesterol) and replace current blood-based methodologies, increasing patient compliance and improve prevention and diagnosis of the disease. As exhaled gases may also reflect changes in cellular function and metabolism, these novel biomarkers may also allow for monitoring cardiovascular and immune system complications of diabetes.